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Drug Delivery System to Improve the Perioperative Administration of Intravenous Drugs: Computer Assisted Continuous Infusion (CACI)

Glass, Peter S. A. MB, ChB; Reves, J. G. MD


Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina.

Accepted for publication May 16, 1995.

Address correspondence and reprint requests to Peter S. A. Glass, Department of Anesthesiology, Box 3094, Duke University Medical Center, Durham, NC 27710.

The provision of appropriate postoperative analgesia should be as important to modern surgery as is intraoperative anesthesia. Potent analgesics, such as morphine, have been available for several hundred years, yet our efficacy in treating acute postoperative pain was until recently abysmal. As late as 1983, 41% of patients rated their pain control inadequate after surgery [1]. The use of self-titration of an analgesic drug to provide postoperative pain management was first achieved in 1968 [2]. The ability to provide self-titration was dependent on developing an appropriate analgesic drug delivery device. It took years for industry to adopt this concept and to develop a commercial device. It also took physicians some time to recognize the utility of this approach to postoperative pain. It did not take patients long to demand patient-controlled analgesia (PCA), which is now widely practiced. There is no doubt that PCA provided a major step forward in the management of acute postoperative pain.

Why has PCA provided a more satisfied patient with improved pain relief? Pain is a very subjective sensation, the effective concentration required for pain relief is extremely variable between patients (pharmacodynamic variability) as well as within patients, and lastly, any given dose will result in a different concentration in each individual due to the unique disposition of the drug in the individual (pharmacokinetic variability). In addition, safety is an issue. Potent opiate analgesics have a very narrow therapeutic margin, with doses exceeding the therapeutic concentration producing significant adverse effects (toxicity). Thus, the objective of any analgesic delivery system is to allow safe individual titration of drug dose so patients can maintain themselves within their own therapeutic window. PCA achieves this objective.

There are, however, some theoretical disadvantages to PCA. Pain is the most intense soon after awakening. Thus, the required concentration of the analgesic is initially high. To attain an effective concentration requires some form of a large initial dose to fill the volume of distribution. To avoid exceeding the therapeutic concentration, multiple small doses of the opiate are given until adequate analgesia is obtained. For opiates like morphine, which equilibrate slowly from the blood to the brain and receptor, this equilibration period can take several hours. Also, due to redistribution and elimination, once the peak effect of the drug is achieved, drug concentration is continuously decreasing. Thus, PCA does not totally avoid the peaks and valleys of intermittent intramuscular injection, but simply makes them smaller.

While PCA has been widely accepted clinical practice, further technologic developments are occurring to further improve drug delivery. Certainly, on a theoretical basis, it is ideal to administer drugs to a target effect (i.e., the clinician sets the targeted effect, e.g., degree of neuromuscular blockade, and the delivery system simply adjusts the dosing rate to achieve this monitored response). Unfortunately, neither anesthesia nor analgesia has readily measurable or quantifiable end-points. Thus, the next best is to be able to administer the drug to an effective concentration. By using pharmacokinetic parameters derived from the disposition of the drug, it is possible to program a computer so that it calculates the dosing regimen necessary to achieve the target plasma concentration (thereby automatically providing the initial loading of the drug) [3]. The efficacy of such devices for the administration of intravenous drugs during anesthesia has been evaluated in many studies over the past 15 yr [3]. Using pharmacokinetic-pharmacodynamic modeling, it is also possible to program the drug delivery device not only to target a plasma concentration but also to target an effect site concentration (i.e., the concentration that is in equilibration with the site of drug effect, e.g., the opiate receptor) [4,5]. This prevents much of the time delay that occurs as the plasma concentration equilibrates with drug receptors in the brain. For example, if a target plasma concentration of fentanyl is selected, it will take approximately 20 min before the full effect of this concentration is observed, whereas if a target effect site concentration is selected the full effect will occur within 3-5 min. Such computer controlled infusion devices [computer assisted continuous infusion (CACI) [6]] can be programmed to almostly instantaneously produce a desired effect concentration and then maintain this concentration. It is a logical step to combine PCA with CACI devices so that patients can rapidly attain and maintain an effective concentration of the analgesic. In this issue of Anesthesia & Analgesia, van den Nieuwenhuyzen et al. [7], although not the first to use such a system, are the first to try to compare the possible advantages of CACI-PCA (referred to as CCIA in their paper) with those of conventional PCA for postoperative pain management. Their results strongly support the superiority of CACI-PCA over conventional patient-controlled administration. This is based on a more rapid achievement of satisfactory analgesia, the time patients spent at the desired level on the visual analog pain scale (VAS; VAS less than 3), and the total number of doses requested by the patient.

The CACI-PCA results favoring target-controlled infusion for PCA need to be carefully reviewed. Unfortunately, the authors chose to compare two different drugs using two different delivery modes. It is difficult to determine whether the advantageous results were due to the drug or the delivery system. Alfentanil has a very rapid onset of effect as evidenced by its ke0 (the ke0 represents the rate of equilibration between the plasma and the effect site). The ke0 for morphine has not been established, but is considered to be considerably longer than that of alfentanil. The more rapid onset of effective analgesia with target-controlled alfentanil could largely be explained by these differences in ke0 rather than the drug delivery system. Similarly, it is noted that the greatest difference in the time period for which there was a VAS of greater than 3 between the two groups was from 0 to 8 h. This again may simply be explained by the slower onset of effective analgesia with morphine compared to alfentanil, rather than the delivery system. In addition, the incremental doses delivered with each demand may not have been truly equally efficacious; thus, it may have required two demands for morphine to provide the same degree of analgesic relief as one demand for alfentanil. This difference would then readily explain the differences in demand and continued differences in time above a VAS of 3 between the two groups.

Of interest and noted by van den Nieuwenhuyzen et al., PCA alfentanil has not provided effective postoperative pain management when given with a conventional PCA device. The authors have demonstrated that when alfentanil is administered using target CACI-PCA for postoperative pain management, it is definitely superior to conventional PCA morphine in providing postoperative pain relief. From this we can infer that through the utilization of CACI-PCA alfentanil becomes a more suitable opiate for postoperative pain management.

One of the primary advantages of CACI drug delivery for postoperative analgesia is that it will maintain the drug level within the therapeutic window for longer periods of time. This argument should similarly hold true when using a low-dose continuous infusion in combination with PCA. The combination of a continuous infusion plus PCA has resulted in a greater number of side effects and greater opiate use but no greater pain relief [8]. A possible explanation for this is that pain, after surgery, does not remain constant, but rather is constantly changing. The advantage of a standard PCA regimen is that no drug is being delivered when pain is decreasing or is minimal. It would therefore seem that the ideal delivery system should rapidly achieve an effective concentration and that this concentration should not necessarily be maintained, but should decrease over time to enable patients to keep themselves within their own changing therapeutic window. van den Nieuwenhuyzen et al. [7] in this study creatively addressed this problem by forcing the target-controlled concentration to decrease after 2 h if no patient demand had been made. Is 2 h an appropriate time interval to wait? CACI drug delivery usually uses a single pharmacokinetic set to represent the entire patient population. van den Nieuwenhuyzen et al. demonstrated that the pharmacokinetics of Maitre et al. [9] provided minimal bias and a low-median absolute performance error. This does not exclude the possibility that in any individual patient, over a 2-h period, the target concentration is increasing with the possibility of significant respiratory depression. When evaluating patients on morphine PCA, the authors' philosophy is to adjust the PCA dose to provide one to two patient-demanded doses per hour. Thus, to wait 2 h without a demand prior to allowing the concentration to decrease may be to wait too long. Fortunately, a CACI drug delivery system can be programmed to start decreasing the target concentration at any specified time. Another feature of CACI-PCA that needs to be addressed is the size of the maintenance dose. Most potent opiates have a very steep concentration effect, so it will be necessary to establish appropriate and safe increments in opiate concentration with each demand. Thus, it is important to first confirm the optimal settings for a CACI delivery system when used in the patient-controlled mode, and then compare this to the traditional bolus method of patient-controlled analgesia using the same drug.

The use of target-controlled drug delivery in a postoperative setting is relatively new. CACI has established itself as an important tool for the intravenous administration of drugs during anesthesia. As a drug delivery system, CACI is akin to the calibrated vaporizer, which is accepted as the standard delivery system for volatile anesthetics. CACI drug delivery has also proven to be more efficacious than intermittent bolus administration and at least equal to a manual infusion system [10]. As a tool CACI has enabled anesthesiologists to define the concentration effect relationship of drugs used in anesthesia, as well as the effect resulting from the interaction between intravenous drugs providing anesthesia [3]. In addition, CACI has enhanced our understanding of the pharmacokinetic and pharmacodynamic principles related to intravenous administration of anesthetic drugs. Like the concept of PCA, target-controlled drug delivery is dependent on having an accessible device. This is largely dependent on industry embracing this concept and providing a commercial device. The paper by van den Nieuwenhuyzen et al. [7] further demonstrates the use and potential of target-controlled drug delivery within our speciality. We predict with certainty and enthusiasm that, when industry and the regulatory agencies produce a CACI device, it will be widely accepted as another step forward in the never-ending quest to optimize patient care.

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